title: Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome.
abstract: OBJECTIVE
  Cerebellar ataxia is commonly observed in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disorder biochemically characterized by ornithine (Orn), homocitrulline (Hcit) and ammonia accumulation. Since the pathophysiology of cerebellum damage in this disorder is still unknown, we investigated the effects of Hcit and Orn on important parameters of redox and energy homeostasis in cerebellum of young rats.
  
  
  METHODS
  We determined thiobarbituric acid-reactive substance (TBA-RS) levels, carbonyl content, nitrate and nitrite production, hydrogen peroxide production, GSH concentrations, sulfhydryl content, as well as activities of respiratory chain complexes I-IV, creatine kinase, Na(+),K(+)-ATPase, aconitase and α-ketoglutarate dehydrogenase.
  
  
  RESULTS
  Orn and Hcit significantly increased TBA-RS levels (lipid oxidation), that was totally prevented by melatonin and reduced glutathione (GSH). We also found that nitrate and nitrite production was not altered by any of the metabolites, in contrast to hydrogen peroxide production which was significantly enhanced by Hcit. Furthermore, GSH concentrations were significantly reduced by Orn and Hcit and sulfhydryl content by Orn, implying an impairment of antioxidant defenses. As regards energy metabolism, Orn and Hcit provoked a significant reduction of aconitase activity, without altering the other parameters. Furthermore, Orn-elicited reduction of aconitase activity was totally prevented by GSH, indicating that the critical groups of this enzyme were susceptible to oxidation caused by this amino acid.
  
  
  CONCLUSIONS
  Taken together, our data indicate that redox homeostasis is disturbed by the major metabolites accumulating in HHH syndrome and that this mechanism may be implicated in the ataxia and cerebellar abnormalities observed in this disorder.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Angela
authors.initials: A
authors.lastname: Zanatta
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Alana Pimentel
authors.initials: AP
authors.lastname: Moura
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004579:Electron Transport; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D022124:Hyperammonemia / Q000378:metabolism* / Q000473:pathology; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009952:Ornithine / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000378:metabolism* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; D009566:Nitrates; D009573:Nitrites; D017392:Thiobarbituric Acid Reactive Substances; C001352:homocitrulline; D002956:Citrulline; D006861:Hydrogen Peroxide; D009952:Ornithine; D007655:Ketoglutarate Dehydrogenase Complex; D003402:Creatine Kinase; D000154:Aconitate Hydratase; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione
keywords: Cerebellum; Homocitrulline; Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; Ornithine; Oxidative stress